Mast cells are frequently found in high numbers at the periphery of solid human and animal tumors, and at other sites of vascularization including wounds, immune reactions and inflammatory sites. Mast cells are also dramatically increased at sites of growing vascular hemangiomas but are reduced when these lesions begin to regress. We have demonstrated that mast cells precede blood vessels to the site of a tumor implant and that the mast cells degranulate at the tumor site and release vasoactive agents. We have also shown that tumors release chemotactic factors for mast cells and that the rates of angiogenesis, tumor growth and tumor metastasis are all reduced in mast cell-deficient mice relative to tumors implanted in control mice. In the current proposal, we will continue these studies, emphasizing the mechanisms by which mast cells accumulate at tumor sites. Because we have identified several agents that are chemotactic for mast cells, we will now investigate whether these factors are able to modulate the amount of angiogenesis that occurs in response to a tumor or purified angiogenic factor. We will also investigate whether any known angiogenic inhibitors may function by interacting with mast cells or with the endothelial response to mast cells. We have obtained partial purification of a potentially novel, low molecular weight factor from bladder carcinoma cells that has potent mast cell chemotactic activity and we will continue our efforts to purify this factor and to obtain amino acid and DNA sequence information regarding this peptide. With regard to hemangiomas, we will study whether cells from these lesions produce mast cell chemoattractants and whether these attractants are similar or different from those released by other tumors. We will also investigate whether alpha-interferon, recently discovered to cause clinical hemangiomas to regress, acts by exerting an effect on mast cells or on endothelial responsiveness to heparin, histamine or other mast cell-derived agents. Finally, because mast cell motility is dependent on mast cell adhesion, we will investigate the nature of the integrin-type adhesion molecules expressed on mucosal- type and connective tissue-type mast cells to determine whether manipulation of mast cell adherence could influence mast cell accumulation at tumor sites and subsequent tumor growth at that site.